The Switch From Paliperidone Long-Acting Injectable 1- to 3-Monthly: Clinical Pharmacokinetic Evaluation in Patients With Schizophrenia (Preliminary Data).

PURPOSE/BACKGROUND: The aim of the study was a preliminary evaluation of the maintenance of clinical efficacy and tolerability of paliperidone palmitate in patients with schizophrenia during the transition phase from 1-monthly paliperidone palmitate formulation (PP1M) to PP3M, with the evaluation of plasma levels of the drug. METHODS/PROCEDURES: A prospective observational study was conducted for 13 months involving 22 outpatients, aged 18 to 66 years and clinically stabilized. Patients were affected by schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria. For each patient, clinical assessment, safety and tolerability, and drug plasma level determination were performed. Clinical efficacy was assessed by Brief Psychiatric Rating Scale, Positive and Negative Symptom Scale, and Hamilton Rating Scale for Depression. During the first 4 months of the study, once-monthly paliperidone palmitate was administered, and then during the following 9 months, the 3-monthly formulation was administered. FINDINGS/RESULTS: The time course of the Brief Psychiatric Rating Scale total scores showed a statistically significant (P = 0.006) improvement from T0 to T8; Positive and Negative Symptom Scale scores showed a similar time course, with a statistically significant (P = 0.0016) reduction of the mean total score; Hamilton Rating Scale for Depression mean scores showed a statistically significant (P = 0.003) reduction with substantial maintenance of clinical stabilization of the patients. Only 1 patient dropped out after the first PP3M injection. IMPLICATIONS/CONCLUSIONS: Our preliminary data currently confirm the maintenance of clinical stability shifting from PP1M to PP3M.

Paliperidone LAI and Aripiprazole LAI Plasma Level Monitoring in the Prophylaxis of Bipolar Disorder Type I with Manic Predominance.

INTRODUCTION: The objective of this study was the evaluation of utility of plasma level monitoring in the clinical stabilizing efficacy and tolerability of paliperidone palmitate (PP) vs. aripiprazole monohydrate (AM) in bipolar disorder I (BD I) with manic predominance. METHODS: Fifty-six outpatients of both sexes, age ranging from 18 to 65 years, affected by BD I with manic predominance, orally treated and stabilized after acute episode for at least 2 weeks with paliperidone or aripiprazole (n=31, paliperidone; n=25, aripiprazole) underwent a prospective observational study of switching to the corresponding long-acting injection (LAI) on the basis of clinical evaluation. The efficacy and tolerability of the 2 treatments were assessed by BPRS, PANSS, HAMD21, and MRS rating scales and a check list every month for 12 months. Drug plasma levels determinations (PLs) were performed at the same times. RESULTS: A good clinical stability and tolerability of both drugs were reported. Lower mean PLs of PP showed a positive effect on depressive symptoms. AM PLs variability was associated with greater instability of manic symptoms whereas intermediate PLs seem to have more influence on depressive symptomatology. DISCUSSION: PLs drug monitoring has been proven to be useful, and further investigations to identify optimal therapeutic ranges for LAI formulations are needed.

Correction to: Clinical Pharmacokinetics of Atypical Antipsychotics: An Update.

The pharmacokinetics of CRP was tested in small short-term studies in both healthy volunteers and in subjects with schizophrenia, with similar results [242].

Aggressiveness and violence in psychiatric patients: a clinical or social paradigm?

OBJECTIVE: Psychiatric disorders are often considered the leading cause of violence. This may be due to a stereotype created by media and general opinion. METHOD: The Modified Overt Aggression Scale (MOAS) was used to evaluate the severity of aggressive and violent behaviors in 400 patients who attended a post-acute psychiatric service in Milan from 2014 to 2016 and suffered from different psychiatric disorders. The psychopathological clinical picture was evaluated by Clinical Global Impression (CGI). The study also assessed the possible correlation between epidemiologic and sociodemographic factors, clinical variables, and aggression and violence. RESULTS: Of the total number of subjects, 21.50% showed a MOAS score >0, 11.50% presented mild aggression (0-10 MOAS weighted score), 9% moderate aggression (11-20), and 1% severe aggression (MOAS >20). With respect to violent behaviors, 16% of patients showed a score >0 in one MOAS subscale other than verbal aggression according to violence definition. The severity of clinical picture seemed to be related to higher weighted MOAS score. Multivariate testing of different sociodemographic and clinical variables showed that violence was related to unemployment status, and significantly correlated to compulsory admission (TSO), suicide attempts (TS), and personality disorders, while the severity of clinical psychiatric picture seemed to play a secondary role. CONCLUSION: Results have shown that personality disorders and sociodemographic factors, including economic factors, seem to be major determinants of violence among patients diagnosed with mental disorders.

Clinical Pharmacokinetics of Atypical Antipsychotics: An Update.

Therapeutic drug monitoring studies have generally concentrated on controlling compliance and avoiding side effects by maintaining long-term exposure to minimally effective blood concentrations. The rationale for using therapeutic drug monitoring in relation to second-generation antipsychotics is still being discussed at least with regard to the real clinical utility, but there is evidence that it can improve efficacy, especially when patients do not respond or develop side effects using therapeutic doses. Furthermore, drug plasma concentration determinations can be of some utility in medico-legal problems. This review concentrates on the clinical pharmacokinetic data related to clozapine, risperidone, paliperidone, olanzapine, quetiapine, amisulpride, ziprasidone, aripiprazole, sertindole, asenapine, iloperidone, lurasidone, brexpiprazole and cariprazine and briefly considers the main aspects of their pharmacodynamics. Optimal plasma concentration ranges are proposed for clozapine, risperidone, paliperidone and olanzapine because the studies of quetiapine, amisulpride, asenapine, iloperidone and lurasidone provide only limited information and there is no direct evidence concerning ziprasidone, aripiprazole, sertindole, brexpiprazole and cariprazine: the few reported investigations need to be confirmed and extended.

Intraindividual and Interindividual Variability of Olanzapine Trough Concentrations in Patients Treated With the Long-Acting Injectable Formulation.

BACKGROUND: A long-acting injectable (LAI) formulation of olanzapine has been developed as an alternative to oral regimens. A therapeutic range of 20 to 80 ng/mL for oral olanzapine trough concentrations has been proposed. Here, we sought to investigate the intraindividual and interindividual variability of olanzapine concentrations with time in patients on maintenance therapy with the LAI formulation carried out in the routine clinical practice. METHODS: To address this issue, we carried out a retrospective analysis of therapeutic drug monitoring of olanzapine concentrations in 21 schizophrenic patients on maintenance LAI olanzapine. Drug concentrations were correlated with LAI olanzapine doses, duration of treatment, and main clinical characteristics. RESULTS: Fifty percent of the patients had olanzapine trough concentrations lower than 20 ng/mL. Only drug doses significantly correlated with olanzapine exposure. Mean interindividual and intraindividual coefficients of variations of olanzapine concentrations were 56% (range, 21%-97%) and 34% (range, 15%-69%), respectively. CONCLUSIONS: We have documented that, in a real-life setting, a large proportion of patients treated with olanzapine LAI had drug trough concentrations of less than 20 ng/mL; wide intraindividual and interindividual variability of olanzapine concentrations has been also observed. Our results could provide the rationale for the design of larger prospective, concentration-controlled clinical trials specifically designed with the goal to identify ad hoc therapeutic ranges of drug concentrations for olanzapine LAI.

Effect of N-Desalkylquetiapine/Quetiapine Plasma Level Ratio on Anxiety and Depression in Bipolar Disorder: A Prospective Observational Study.

BACKGROUND: The aim of this study was to analyze the relationships between quetiapine and N-desalkylquetiapine plasma levels and clinical improvement, particularly, in regard to depressive and anxious symptoms and to hostility. METHODS: This was a prospective observational study that involved 37 outpatients diagnosed as having bipolar disorder I or II. All the patients were observed during a clinical acute and postacute phase. Patients were prescribed 50-800 mg of quetiapine. Patients were evaluated at baseline, after 15 days and after 3 months using the Brief Psychiatry Rating Scale with particular reference to the dimensions of depression, anxiety, and hostility. The plasma concentrations of quetiapine and N-desalkylquetiapine were determined after 3 months using blood samples taken at steady state. RESULTS: There was a significant relationship between the N-desalkylquetiapine/quetiapine ratio and the improvement in the depression dimension, and there was not a significant relationship between the N-desalkylquetiapine/quetiapine ratio and anxiety and hostility improvement. Quetiapine treatment was well tolerated, and there were no extrapyramidal, anticholinergic, or other side effects to note. There was no relationship between plasma quetiapine or N-desalkylquetiapine concentrations and side effects. CONCLUSIONS: Our findings confirm the efficacy of quetiapine on depressive symptoms, and the available data support that quetiapine's antidepressant activity is mediated by the active metabolite norquetiapine, and it exemplifies the case of an active metabolite that can make a drug like quetiapine originally introduced as an antipsychotic a useful antidepressant agent.

Paliperidone Long-Acting Plasma Level Monitoring and a New Method of Evaluation of Clinical Stability.

The second generation long-acting antipsychotics can be a pharmacologic strategy, both in the early phase of illness and in the case of low compliance. The aim of the study was to evaluate the clinical efficacy and tolerability of one monthly injection of paliperidone palmitate (PP1M), paliperidone plasma levels (PLs), and the clinical outcome. 21 outpatients, affected by Schizophrenia or Schizoaffective Disorder, were recruited. PP1M started with 150 mg on day 1 and 100 mg on day 8. Following patients were given a dosage ranging from 50 mg to 150 mg every 28 days. At baseline, and then monthly, patients were clinically evaluated. BPRS and PANSS total score showed a statistically significant decrease from T2 (after 2 months) to T12 (after 12 months). The PLs steady-state was approximatively reached after the fifth injection (T4). All the patients showed a clinical stabilization: BPRS and PANSS scores showed a significant improvement from T2. PLs data seems to suggest the initial possibility of an oral supplementation, although clinical evaluation demonstrated no relapse during the study.

Gray matter volumes may predict the clinical response to paliperidone palmitate long-acting in acute psychosis: A pilot longitudinal neuroimaging study.

In schizophrenia, paliperidone palmitate (PP) long acting injectable (LAI) has been reported to sustain plasma concentrations and improve clinical symptoms. Moreover, it has also been demonstrated the important role of total gray matter (GM) volumes in predicting the clinical outcome. However, no studies investigating the association between PP-LAI treatment and brain morphometry has been published so far. Therefore, the main aim of our 24 weeks prospective observational exploratory study was to investigate the relation between brain anatomy and clinical outcome in seven patients with acute psychosis treated with PP-LAI. At baseline and every month (from T0 to T6) patients were clinically evaluated with the Brief Psychiatric Rating Scale (BPRS). 3T Magnetic Resonance Imaging at baseline was acquired and total GM and intracranial volumes were extracted to explore their predictive values on BPRS scores. After 24 weeks of treatment with PP-LAI, patients showed statistically significant improvements in BPRS scores. Moreover, subjects with higher total GM volumes had a significantly higher BPRS improvement at 24 weeks compared to patients with lower total GM volumes. Our findings confirm the effectiveness of PP-LAI in treating acute psychosis and suggest that greater GM volumes predict drug response, potentially supporting a favorable prognosis.

Duloxetine in elderly major depression disorder: effectiveness and drug plasma level evaluation.

OBJECTIVE: The aim of this open-label naturalistic study was to assess clinical outcomes and the predictive value of duloxetine plasma levels in major depressive disorder in the elderly. METHODS: This naturalistic, open-label design involved 35 outpatients aged between 65 and 87 years. Duloxetine plasma levels were collected in 24 patients after the first month. Patients were evaluated using 21-item Hamilton Rating Scales for Depression, Hamilton Rating Scales for Anxiety, the Clinical Global Impression Severity, Mini Mental State Examination, Cumulative Illness Rating Scale, Barthel Index and Beck's Depression Inventory. RESULTS: Duloxetine plasma levels at T2 ranged from 4.9 to 201.9 ng/mL without a significant correlation between duloxetine dose and plasma levels. A significant improvement in mean 21-item Hamilton Rating Scales for Depression total scores at T2,T3, T4, T9 and T12 and a progressive significantly decrease of the mean Hamilton Rating Scales for Anxiety scores from T3 to T12 were observed. CONCLUSIONS: The levels of duloxetine in plasma do not correlate with a greater clinical improvement, indeed appear to adversely affect the improvement of the Beck Depression Inventory and Hamilton Rating Scales for Anxiety. This could be explained by an increase in side effects that may aggravate the discomfort felt by the patient. Copyright © 2016 John Wiley & Sons, Ltd.

"Long-acting" olanzapine in maintenance therapy of schizophrenia: A study with plasma levels.

INTRODUCTION: This prospective study was performed to evaluate clinical efficacy and tolerability of olanzapine long-acting injection (OLZ-LAI) and the relation between OLZ plasma level (PL) and the clinical outcome in maintenance therapy of schizophrenia. MATERIAL AND METHODS: Twenty-five chronic schizophrenic outpatients with age ranging from 18 to 65 years were included in this 9-month study. Patients were given a dosage of either 210 or 300 or 405 mg of OLZ-LAI every 28 days. Patients were evaluated at baseline and every four weeks by Brief Psychiatric Rating Scale (BPRS) and Positive and Negative Symptom Scale (PANSS); at the same time, PL of OLZ was determined. The metabolic profile (aspartate aminotransferase, alanine aminotransferase, high-density lipoprotein, low-density lipoprotein, total cholesterol, and glucose levels) was analyzed every two months. RESULTS: BPRS and total PANSS showed a statistically significant improvement from T2 with a clinical stabilization of psychopathological picture. PL ranged from 4.0 to 78.9 ng/ml (mean 20.59 ng/ml ± 14.66 standard deviation). The coefficient of variation of PLs was related to clinical stabilization. No post-injection delirium sedation syndrome occurred. CONCLUSIONS: Our data reveal the efficacy of OLZ-LAI in maintenance treatment of schizophrenia at lower dosages also in comparison with that of oral therapy. OLZ-LAI seems to be useful for guaranteeing constant PL of the drug. A lesser variation of PL was the most predictable factor associated with maintenance of clinical benefit.